Induction and exacerbation of emphysema in hamsters with human neutrophil elastase inactivated reversibly by a peptide boronic acid.
In solution, MeO-Suc-Ala-Ala-Pro-D,L-boro-Val pinacol ester (Boroval) is a highly effective but reversible inhibitor of both porcine pancreatic elastase and human neutrophil elastase (HNE) (50% inhibition with a 1.5 M ratio of Boroval to elastase). Boroval has been shown to prevent porcine-pancreatic-elastase-induced emphysema in hamsters. But with HNE-induced emphysema in hamsters, pretreatment with as much as a 170-fold M excess of Boroval, given intratracheally 1 h before 0.3 mg HNE, did not prevent emphysema. Indeed, lung volumes were larger after Boroval pretreatment than after HNE alone. Emphysema was also induced by instilling HNE that had been mixed with and inactivated by a 41-fold M excess of Boroval (a molar ratio of 42). When 0.25 or 0.5 mg of HNE were given mixed with a 41-fold M excess of Boroval, the emphysema was much more severe with the 0.5 mg dose. Two hours after instillation of 0.3 mg HNE inactivated with a 34-fold M excess of Boroval, bronchoalveolar lavage contained elastolytic activity but no evidence of hemorrhage. In contrast, hemorrhage was severe in hamsters that had been instilled with 0.3 mg HNE alone. We conclude that Boroval can enhance HNE-induced emphysema. We postulate that Boroval suppresses HNE-induced hemorrhage and the resultant influx of plasma protease inhibitors; the HNE-Boroval complex is transported into the alveolar interstitium, followed by dissociation of the inhibitor from the active site of HNE. Because of its small size, free Boroval is rapidly cleared, and the reactivated HNE attacks elastic fibers, giving rise to emphysema.
Stone
P J
PJ
Department of Biochemistry, Boston University School of Medicine, MA 02118.
Lucey
E C
EC
Snider
G L
GL
D000818:Animals; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000201:enzymology; D006224:Cricetinae; D006470:Hemorrhage / Q000139:chemically induced; D019272:Leukocyte Elastase; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D008176:Lung Volume Measurements; D008297:Male; D008647:Mesocricetus; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology
D001897:Boronic Acids; D009842:Oligopeptides; C048437:methyl-O-succinyl-alanyl-alanyl-prolyl-borovaline-pinacol; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase